PRKN : parkin RBR E3 ubiquitin protein ligase

Description

The PRKN (parkin RBR E3 ubiquitin protein ligase) is a protein-coding gene located on chromosome 6.

The PRKN gene, one of the largest human genes, provides instructions for making a protein called parkin. Parkin plays a role in the cell machinery that breaks down (degrades) unneeded proteins by tagging damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to move unneeded proteins into specialized cell structures known as proteasomes, where the proteins are degraded. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the availability of proteins that are involved in several critical cell activities, such as the timing of cell division and growth. Because of its activity in the ubiquitin-proteasome system, parkin belongs to a group of proteins called E3 ubiquitin ligases. Parkin appears to be involved in the maintenance of mitochondria, the energy-producing centers in cells. However, little is known about its role in mitochondrial function. Research suggests that parkin may help trigger the destruction of mitochondria that are not working properly. Studies of the structure and activity of parkin have led researchers to propose several additional activities for this protein. Parkin may act as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way. Parkin may also regulate the supply and release of sacs called synaptic vesicles from nerve cells. Synaptic vesicles contain chemical messengers that transmit signals from one nerve cell to another.

PRKN, also known as Parkin RBR E3 ubiquitin-protein ligase or Parkinson juvenile disease protein 2, functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Its substrates include SYT11, VDAC1, BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2. PRKN mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. It participates in the removal and/or detoxification of abnormally folded or damaged proteins by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7. 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation. PRKN mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation. It mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. PRKN protects against mitochondrial dysfunction during cellular stress, by acting downstream of PINK1 to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components. Depending on the severity of mitochondrial damage and/or dysfunction, its activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy. Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin. After mitochondrial damage, PRKN functions with PINK1 to mediate the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 promotes mitophagy, while monoubiquitination of VDAC1 decreases mitochondrial calcium influx which ultimately inhibits apoptosis. When cellular stress results in irreversible mitochondrial damage, PRKN promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, MFN1 and USP30. It preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy. The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2. This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes. PRKN regulates motility of damaged mitochondria via the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma. PRKN is involved in mitochondrial biogenesis via the 'Lys-48'-linked polyubiquitination of transcriptional repressor ZNF746/PARIS which leads to its subsequent proteasomal degradation and allows activation of the transcription factor PPARGC1A. PRKN limits the production of reactive oxygen species (ROS). It regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, PRKN may enhance cell viability and protect cells from oxidative stress. Independently of its ubiquitin ligase activity, PRKN protects from apoptosis by the transcriptional repression of p53/TP53. It may protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. PRKN may play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. It may represent a tumor suppressor gene. PRKN forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6. It mediates 'Lys-63'-linked polyubiquitination by associating with UBE2V1. PRKN is part of a SCF-like complex, consisting of PRKN, CUL1 and FBXW7. It interacts with SNCAIP, binds to the C2A and C2B domains of SYT11, interacts and regulates the turnover of SEPTIN5, and is part of a complex, including STUB1, HSP70 and GPR37. The amount of STUB1 in the complex increases during ER stress. STUB1 promotes the dissociation of HSP70 from PRKN and GPR37, thus facilitating PRKN-mediated GPR37 ubiquitination. HSP70 transiently associates with unfolded GPR37 and inhibits the E3 activity of PRKN, whereas, STUB1 enhances the E3 activity of PRKN through promotion of dissociation of HSP70 from PRKN-GPR37 complexes. PRKN interacts with PSMD4 and PACRG, LRRK2, RANBP2, SUMO1 but not SUMO2, which promotes nuclear localization and autoubiquitination, AIMP2 (via first RING-type domain), PSMA7 and RNF41, PINK1, and forms a complex with PINK1 and PARK7. PRKN interacts with CHPF, the interaction with isoform 2 may facilitate PRKN transport into the mitochondria. PRKN interacts with MFN2 (phosphorylated), promotes PRKN localization in dysfunctional depolarized mitochondria. It interacts with FBXO7; this promotes translocation to dysfunctional depolarized mitochondria. PRKN interacts with ZNF746, heat shock protein 70 family members, including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes translocation to damaged mitochondria. It interacts with BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits translocation to damaged mitochondria. It forms a complex with PRKN and PARK7. PRKN interacts with AMBRA1.

PRKN is also known as AR-JP, LPRS2, PARK2, PDJ.

Associated Diseases

Comprehensive carrier screening